Metabolism carboxylic acids

Mihaly et al. [128] identified the carboxylic acid derivative of primaquine as a major plasma metabolite. After oral administration of 45 mg of primaquine to healthy volunteers, absorption of the drug was rapid, with peak primaquine levels of 153.3 ng/mL at 3 h, followed by an elimination half-life of 7.1 h, systemic clearance of 21.1 L/h, volume of distribution of 205 L and cumulative urinary excretion of 1.3% of the dose. Primaquine was converted rapidly to the carboxylic acid metabolic, which achieved peak levels of 1427 ng/mL at 7 h. 

Very important compounds are the carboxylic acids and their derivatives, which can be formally obtained by exchanging the OH group for another group. In fact, derivatives of this type are formed by nucleophilic substitutions of activated intermediate compounds and the release of water (see p. 14). Carboxylic acid esters (R-O-CO-R ) arise from carboxylic acids and alcohols. This group includes the fats, for example (see p.48). Similarly, a carboxylic acid and a thiol yield a thioester (R-S-CO-R ). Thioesters play an extremely important role in carboxylic acid metabolism. The best-known compound of this type is acetyl-coenzyme A (see p. 12). 

Thioesters of coenzyme A (D 11) are important intermediates in carboxylic acid metabolism. They are formed by acid-tbiol bgases (thiokinases) either via acyl phosphates ... 

In man, the metabolic pathways of mepirizole were distinct from those in experimental animals, since hydroxylation on each of the aromatic rings did not occur in man. Compound (752) was obtained by oxidation of the 3-methyl group to the carboxylic acid (a similar process occurs with 5-methylpyrazole-3-carboxylic acid, an active metabolite of 3,5-dimethylpyrazole). However, the carboxylic acid metabolite of mepirizole had no analgesic activity and did not decrease blood glucose. 

Yet another nonsedating zwitterionic H-1 antihistamine consists of the product from metabolism of the terminal hydroxyl of the potent antihistamine hydroxyzine terminating in hydroxymethyl instead of a carboxylic acid. This compound, cetirzine (123), can be obtained in straightforward fashion by alkylation of the monosubstituted piperazine 120 with halide 121, via the amide 122 [27]. 

The latter approach is used in the enantioselective determination of a Phase I metabolite of the antihistaminic drug, terfenadine. Terfenadine is metabolized to several Phase I compounds (Fig. 7-13), among which the carboxylic acid MDL 16.455 is an active metabolite for which plasma concentrations must often be determined. Although terfenadine can be separated directly on Chiralpak AD - an amy-lose-based CSP - the adsorption of the metabolite MDL 16.455 is too high to permit adequate resolution. By derivatizing the plasma sample with diazomethane, the carboxylic acid is converted selectively to the methyl ester, which can be separated in the presence of all other plasma compounds on the above-mentioned CSP Chiralpak AD [24] (Fig. 7-14). Recently, MDL 16.455 has been introduced as a new antihistaminic drug, fexofenadine. 

Compounds called carboxylic acids, which contain the -C02H grouping, occur abundantly in all living organisms and are involved in almost all metabolic pathways. Acetic acid, pyruvic acid, and citric acid are examples. 

Water can add reversibly to o ,/3-unsalurated aldehydes and ketones to yield /3-hydroxy aldehydes and ketones, although the position of the equilibrium generally favors unsaturated reactant rather than saturated adduct. A related addition to an c /S-unsaturated carboxylic acid occurs in numerous biological pathways, such as the citric acid cycle of food metabolism where ds-aconitate is converted into isocitrate by conjugate addition of water to a double bond. 

Tazarotene (Table 1) is an acetylenic third generation retinoid derivative. It is a poorly absorbed, nonisome-risable arotinoid, which is rapidly metabolized to its free carboxylic acid, tazarotenic acid, binding with high affinity to RARs, with the rank order of affinity being... 

Trace Amines. Figure 1 The main routes of trace amine metabolism. The trace amines (3-phenylethylamine (PEA), p-tyramine (TYR), octopamine (OCT) and tryptamine (TRP), highlighted by white shading, are each generated from their respective precursor amino acids by decarboxylation. They are rapidly metabolized by monoamine oxidase (MAO) to the pharmacologically inactive carboxylic acids. To a limited extent trace amines are also A/-methylated to the corresponding secondary amines which are believed to be pharmacologically active. Abbreviations AADC, aromatic amino acid decarboxylase DBH, dopamine b-hydroxylase NMT, nonspecific A/-methyltransferase PNMT, phenylethanolamine A/-methyltransferase TH, tyrosine hydroxylase. 

As a hypothesis to explain his observations, Krugerl3 proposed (as is shown in scheme 3 along with other hypothesis) that the derived 3-ketonitrosamine underwent a cleavage reaction to yield a methylalkylnitrosamine and a carboxylic acid derivative, in analogy to fatty acid metabolism. 

A number of carboxylic acids are found in nature and also present in metabolic pathways. Accordingly, if monobasic acids are smoothly decarboxylated, they are expected to provide us with new routes to supply useful materials for chemical industry without depending on petroleum. Actually, there are some already known examples. The representative examples are the decarboxylation of cinnamic acid derivatives (Table 8). ... 

Bauer G, F Lingens (1992) Microbial metabolism of quinoline and related compounds XV. Quinoline-4-carboxylic acid oxidoreductase from Agrobacterum spec. IB a molybdenum-containing enzyme. Biol Chem Hoppe-Seyler 370 1183-1189. 

Stable metabolic associations generally between pairs of anaerobic bacteria have been termed syntrophs, and these are effective in degrading a number of aliphatic carboxylic acids or benzoate under anaerobic conditions. These reactions have been discussed in reviews (Schink 1991, 1997 Lowe et al. 1993) that provide lucid accounts of the role of syntrophs in the degradation of complex organic matter. Two examples are given here to illustrate the experimental intricacy of the problems besetting the study of syntrophic metabolism under anaerobic conditions ... 

The application of substrates isotopically labeled in specific positions makes it possible to follow the fate of individual atoms during the microbial degradation of xenobiotics. Under optimal conditions, both the kinetics of the degradation, and the formation of metabolites may be followed— ideally when samples of the labeled metabolites are available. Many of the classical studies on the microbial metabolism of carbohydrates, carboxylic acids, and amino acids used radioactive... 

Hydrolysis to the diol followed by dehydration to the aldehyde and oxidation to the carboxylic acid is used by a propene-utilizing species of Nocardia (de Bont et al. 1982). Although an ethene-utilizing strain of Mycobacterium sp. strain E44 degrades ethane-l,2-diol by this route, the diol is not an intermediate in the metabolism of the epoxide (Wiegant and de Bont 1980). 

Taylor DG, PW Trudgill (1978) Metabolism of cyclohexane carboxylic acid by Alcaligenes strain Wl. / Bacteriol 134 401-411. 

Reiner AM, GD Hegeman (1971) Metabolism of benzoic acid by bacteria. Accumulation of (-)-3,5-cyclo-hexadiene-l,2-diol-l-carboxylic acid by a mutant strain of Alcaligenes eutrophus. Biochemistry 10 2530-2536. 

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